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3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3

Inhibition of the key glycolytic activator 6-phosphofructokinase 2/fructose-2,6-bisphosphatase-3 (PFKFB3) by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) strongly attenuates pathological angiogenesis in cancer and inflammation. In addition to modulating endothelial proliferation and migratio...

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Autores principales: Wik, Jonas Aakre, Lundbäck, Peter, la Cour Poulsen, Lars, Haraldsen, Guttorm, Skålhegg, Bjørn Steen, Hol, Johanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055879/
https://www.ncbi.nlm.nih.gov/pubmed/32130250
http://dx.doi.org/10.1371/journal.pone.0229395
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author Wik, Jonas Aakre
Lundbäck, Peter
la Cour Poulsen, Lars
Haraldsen, Guttorm
Skålhegg, Bjørn Steen
Hol, Johanna
author_facet Wik, Jonas Aakre
Lundbäck, Peter
la Cour Poulsen, Lars
Haraldsen, Guttorm
Skålhegg, Bjørn Steen
Hol, Johanna
author_sort Wik, Jonas Aakre
collection PubMed
description Inhibition of the key glycolytic activator 6-phosphofructokinase 2/fructose-2,6-bisphosphatase-3 (PFKFB3) by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) strongly attenuates pathological angiogenesis in cancer and inflammation. In addition to modulating endothelial proliferation and migration, 3PO also dampens proinflammatory activation of endothelial cells and experimental inflammation in vivo, suggesting a potential for 3PO in the treatment of chronic inflammation. The aim of our study was to explore if the anti-inflammatory action of 3PO in human endothelial cells was mediated by inhibition of PFKFB3 and glycolysis and assess if other means of PFKFB3 inhibition reduced inflammatory activation in a similar manner. We found that 3PO caused a rapid and transient reduction in IL-1β- and TNF-induced phosphorylation of both IKKα/β and JNK, thus inhibiting signaling through the NFκB and the stress-activated kinase pathways. However, in contrast to 3PO-treatment, neither shRNA-mediated silencing of PFKFB3 nor treatment with the alternative PFKFB3 inhibitor 7,8-dihydroxy-3-(4-hydroxy-phenyl)-chromen-4-one (YN1) prevented cytokine-induced NFκB signaling and upregulation of the adhesion molecules VCAM-1 and E-selectin, implying off target effects of 3PO. Collectively, our results suggest that the anti-inflammatory action of 3PO in human endothelial cells is not limited to inhibition of PFKFB3 and cellular glycolysis.
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spelling pubmed-70558792020-03-13 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3 Wik, Jonas Aakre Lundbäck, Peter la Cour Poulsen, Lars Haraldsen, Guttorm Skålhegg, Bjørn Steen Hol, Johanna PLoS One Research Article Inhibition of the key glycolytic activator 6-phosphofructokinase 2/fructose-2,6-bisphosphatase-3 (PFKFB3) by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) strongly attenuates pathological angiogenesis in cancer and inflammation. In addition to modulating endothelial proliferation and migration, 3PO also dampens proinflammatory activation of endothelial cells and experimental inflammation in vivo, suggesting a potential for 3PO in the treatment of chronic inflammation. The aim of our study was to explore if the anti-inflammatory action of 3PO in human endothelial cells was mediated by inhibition of PFKFB3 and glycolysis and assess if other means of PFKFB3 inhibition reduced inflammatory activation in a similar manner. We found that 3PO caused a rapid and transient reduction in IL-1β- and TNF-induced phosphorylation of both IKKα/β and JNK, thus inhibiting signaling through the NFκB and the stress-activated kinase pathways. However, in contrast to 3PO-treatment, neither shRNA-mediated silencing of PFKFB3 nor treatment with the alternative PFKFB3 inhibitor 7,8-dihydroxy-3-(4-hydroxy-phenyl)-chromen-4-one (YN1) prevented cytokine-induced NFκB signaling and upregulation of the adhesion molecules VCAM-1 and E-selectin, implying off target effects of 3PO. Collectively, our results suggest that the anti-inflammatory action of 3PO in human endothelial cells is not limited to inhibition of PFKFB3 and cellular glycolysis. Public Library of Science 2020-03-04 /pmc/articles/PMC7055879/ /pubmed/32130250 http://dx.doi.org/10.1371/journal.pone.0229395 Text en © 2020 Wik et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wik, Jonas Aakre
Lundbäck, Peter
la Cour Poulsen, Lars
Haraldsen, Guttorm
Skålhegg, Bjørn Steen
Hol, Johanna
3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3
title 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3
title_full 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3
title_fullStr 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3
title_full_unstemmed 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3
title_short 3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3
title_sort 3po inhibits inflammatory nfκb and stress-activated kinase signaling in primary human endothelial cells independently of its target pfkfb3
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055879/
https://www.ncbi.nlm.nih.gov/pubmed/32130250
http://dx.doi.org/10.1371/journal.pone.0229395
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